Multiple myeloma (MM) affected 14,400 new patients with in the United States in 2001, with 50,000 total patients, and unfortunately remains incurable despite conventional and high dose chemotherapy. In past studies sponsored by this grant in our Jerome Lipper Multiple Myeloma Center, we have characterized the role of growth factors in MM pathogenesis and derived novel therapies to improve patient outcome based upon targeting cytokines and their signaling cascades both in the MM cell as well as its bone marrow (BM) microenvironment. To achieve this goal, we have developed systems for studying the growth, survival, and drug resistance mechanisms intrinsic to MM cells. Importantly, we have also developed both in vitro systems and in vivo animal models to characterize mechanisms of MM cell homing to BM, as well as cytokines promoting MM cell growth and drug resistance in the BM milieu. These model systems have allowed for the development of several promising biologically-based therapies, including thalidomide (Thal) and its immunomodulatory analogs (IMiDs), proteasome inhibitor PS 341, and arsenic trioxide (As2O3). Once preclinical promise has been demonstrated, we have rapidly translated these laboratory studies to phase I and II clinical trials to evaluate their clinical utility and toxicity. Importantly, ongoing gene array studies of samples obtained from patients treated on these protocols is directed to identify in vivo targets and mechanisms of drug action on the one hand, versus mechanisms of drug resistance on the other. These studies have suggested the critical role of cytokines in growth, survival, drug resistance, and migration of MM cells, providing the framework for validating their role in MM pathogenesis and as targets for novel therapies, as proposed in this competitive renewal application with the following three specific aims: Specific Aim 1 To characterize the role of growth factors in mediating growth, survival, drug resistance, and migration of MM cells in vitro; Specific Aim 2 To validate the signaling events mediating cytokine-induced growth, survival, drug resistance, and migration of MM cells as therapeutic targets; and Specific Aim 3 To validate novel therapeutics targeting in vivo cytokine-induced signaling cascades in animal models for evaluation in phase I/II clinical trials.